Disrupted antiviral immune responses are associated with severe COVID-19 MESHD
, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c PROTEIN
of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c PROTEIN
degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c PROTEIN
. Our study indicated that ORF9c PROTEIN
enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle.
One-sentence summarySARS-CoV-2 ORF9c PROTEIN
is the first human coronavirus protein localized to membrane, suppressing antiviral response, resembling full viral infection.